One of the most under explored and yet devastating consequences of cancer is cachexia, a condition in which the body is consumed by deranged carbohydrate, lipid and protein metabolism induced by inflammatory cytokines secreted systemically, and by the tumor. Cachexia is the cause for 20-40% of all cancer related deaths. A weight loss of 5% over 3 to 6 months is associated with poor treatment outcome, fatigue and poor quality of life, and a weight loss of 30% is frequently lethal. The ability to reverse or control this condition would have a tremendous impact on treatment outcome, quality of life, and mortality, but to date there are no known cures for this condition. Because of the multi-factorial characteristics of this condition, it has been difficult to understand the impact of the tumor on body organs, and the sequence of events that leads to this lethal condition. Such insights are critically important in identifying therapeutic strategies, especially in this decade of molecular targeted medicine. The ability to understand the interaction between the tumor and normal tissues and noninvasively image the sequence of development of this condition would be invaluable in identifying critical stages when the condition becomes life-threatening. Current multi-modality molecular and functional imaging capabilities provide unique opportunities to study cachexia holistically in preclinical models and clinically. In this exploratory application, we will use state-of-the art imaging techniques in combination with molecular characterization to understand cancer-induced cachexia and the cachexia cascade in preclinical models. Imaging indices identified in these preclinical studies can, in the future, be translated to detect the development of the cachexia cascade in patients. Depending on the metabolic targets identified, image-guided siRNA delivery can be used in future studies to down-regulate pathways and understand their impact on the cachexia cascade. PUBLIC HEALTH RELEVANCE: Cachexia induced by cancer is one of the most under explored and yet devastating consequences of cancer, and is the cause for 20-40% of all cancer related deaths. Cachexia-induced weight loss of 5% over 3 to 6 months is associated with poor treatment outcome, fatigue and poor quality of life, and a weight loss of 30% is frequently lethal. The ability to reverse or control this condition would have a tremendous impact on treatment outcome, quality of life, and mortality, but to date there are no known cures for this condition. In this exploratory application, we will use state-of-the art imaging techniques in combination with molecular characterization to understand cancer-induced cachexia and the cachexia cascade in preclinical tumor models.